The rapid development of potent antiretroviral (ARV) therapy for HIV disease has led to the dramatic reduction in new AIDS cases and HIV-related mortality in the United States. Despite these promising trends, significant uncertainty exists on the optimal use of ARV therapy. In addition, increasing momentum exists among government and world health organizations to expand ARV use in less developed nations. Ideal and feasible regimens and approaches in this setting have yet to be determined. For over a decade, I have designed and conducted clinical trials of HIV therapies and pathogenesis. My current career goals include: a) innovative translational patient based research; b) increased mentorship role; and c) development of an international based program. At the UCSD Antiviral Research Center (AVRC), excellent facilities exist to implement proposed studies. A rich and diverse faculty cooperates in an active and productive HIV research group. Active fellowship and clinical research training programs at UCSD provide the opportunity to mentor junior investigators in patient orientated research. Affiliations with universities In Uganda and India afford opportunities to develop an international program. Three hypothesis based clinical trials are presented as the basis for career growth and development. In the first trial, ARV "intensification" is applied to a very well characterized cohort of individuals who have viral suppression for over 5 years. Rates of RNA and DNA decay will be determined, providing insight into sources of ongoing viral replication. In the second trial, ARV "interruption" will be utilized in a large randomized trial of patients failing ARV therapy with drug resistant virus to determine if repopulation with drug sensitive virus enhances response to a new ARV regimen. The third trial is an international study of "punctuated" ARV in Uganda for patients with tuberculosis and HIV. This randomized study is designed to test the hypothesis that HIV disease progression in patients with tuberculosis and a high CD4 cell counts can be delayed with a brief ARV course.